tbuckley/cabot-search huggingface dataset:
Assessment of Oncology Advanced Practice Professional Willingness to Participate in Medical Aid in Dying
Authors: Jonathan Singer, Courtney Daum, Megan J. Shen, Gabrielle Zecha, Louise Kaplan, Kathy Plakovic, Meagan Blazey, Molly Arnold, Barbara Silko, Kelsey Baker, Elizabeth T. Loggers
Journal: JAMA Network Open (2022)

Importance In 2021, New Mexico passed legislation allowing nurse practitioners and physician assistants (referred to herein as advanced practice professionals [APPs]) to prescribe medications for medical aid in dying (MAID). Other US states with existing MAID laws (eg, Washington) are also considering expanding MAID prescribing authority to APPs. There is a lack of research exploring APP knowledge of, willingness to, and comfort with acting as a prescribing or consulting clinician for MAID. Objective To assess perspectives of oncology APPs regarding MAID, including their willingness to prescribe and/or consult for MAID and factors associated with willingness. Design, Setting, and Participants This cross-sectional, self-report survey study used data collected from APPs working at a comprehensive cancer center in Washington State in fall 2021. Main Outcomes and Measures The primary survey question was whether APPs would be willing to participate in death with dignity, the term used for MAID in Washington. Survey questions evaluated how influential specific factors were on APP views on MAID as well as respondents’ knowledge of and comfort with aspects of the MAID process. Results Of 167 eligible APPs, 77 (46.1%) responded to the survey. Most respondents (68 [88.3%]) reported their race and ethnicity as White; 72 (93.5%) identified as a woman. Medical oncology (28 [36.4%]) was the most common field of practice, and 21 respondents (27.3%) reported having practiced as an APP for 6 to 10 years. Of all respondents, 61 (79.2%) reported having at least 1 patient who inquired about MAID; depending on the question, less than a third of respondents (5.0%-27.0%) endorsed feeling knowledgeable or very knowledgeable about any aspect of the MAID process. In this study, 39 APPs (50.6%) endorsed being willing to participate in MAID either as a consulting or prescribing clinician, whereas 31 (40.3%) were uncertain of whether they would participate. Willingness to participate was associated with having had more patients pursue MAID (33 of the 39 willing participants [84.6%] vs 15 of the 31 unsure participants [48.4%] reported having 1 or more patients pursue MAID). Higher knowledge and comfort scores were both significantly associated with increased odds of being willing to participate (odds ratio, 1.14 per 1-point score increase [95% CI, 1.03-1.27]; P = .01) vs unsure (1.18 [95% CI, 1.07-1.30; P = .001). Conclusions and Relevance The results of this survey study suggest that oncology APPs may require preparation for the addition of MAID to their scope of practice. This study also raises questions for future research regarding support for APPs who may be considering participation in MAID but question their role or want physician involvement.
Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma
Authors: Coral Halperin, Joschka Hey, Dieter Weichenhan, Yaniv Stein, Shimrit Mayer, Pavlo Lutsik, Christoph Plass, Ruth Scherz-Shouval
Journal: Cancer Research (2022)

Abstract Cancer cells recruit and rewire normal fibroblasts in their microenvironment to become protumorigenic cancer-associated fibroblasts (CAF). These CAFs are genomically stable, yet their transcriptional programs are distinct from those of their normal counterparts. Transcriptional regulation plays a major role in this reprogramming, but the extent to which epigenetic modifications of DNA also contribute to the rewiring of CAF transcription is not clear. Here we address this question by dissecting the epigenetic landscape of breast CAFs. Applying tagmentation-based whole-genome bisulfite sequencing in a mouse model of breast cancer, we found that fibroblasts undergo massive DNA methylation changes as they transition into CAFs. Transcriptional and epigenetic analyses revealed RUNX1 as a potential mediator of this process and identified a RUNX1-dependent stromal gene signature. Coculture and mouse models showed that both RUNX1 and its stromal signature are induced as normal fibroblasts transition into CAFs. In breast cancer patients, RUNX1 was upregulated in CAFs, and expression of the RUNX1 signature was associated with poor disease outcome, highlighting the relevance of these findings to human disease. This work presents a comprehensive genome-wide map of DNA methylation in CAFs and reveals a previously unknown facet of the dynamic plasticity of the stroma. Significance: The first genome-wide map of DNA methylation in breast cancer–associated fibroblasts unravels a previously unknown facet of the dynamic plasticity of the stroma, with far-reaching therapeutic implications.
Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of <i>Subdoligranulum</i>
Authors: Meagan E. Chriswell, Adam R. Lefferts, Michael R. Clay, Alex Ren Hsu, Jennifer Seifert, Marie L. Feser, Cliff Rims, Michelle S. Bloom, Elizabeth A. Bemis, Sucai Liu, Megan D. Maerz, Daniel N. Frank, M. Kristen Demoruelle, Kevin D. Deane, Eddie A. James, Jane H. Buckner, William H. Robinson, V. Michael Holers, Kristine A. Kuhn
Journal: Science Translational Medicine (2022)

The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast–derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae . After generating bacterial isolates within the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum from the feces of an individual, we confirmed monoclonal antibody binding and CD4 + T cell activation in individuals with RA compared to control individuals. In addition, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated T H 17 cell expansion, serum RA–relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4 + T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.
Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia
Authors: Giorgio Ottaviano, Christos Georgiadis, Soragia Athina Gkazi, Farhatullah Syed, Hong Zhan, Annie Etuk, Roland Preece, Jan Chu, Agnieszka Kubat, Stuart Adams, Paul Veys, Ajay Vora, Kanchan Rao, Waseem Qasim, Jesmina James, Kimberly Gilmour, Sarah Inglott, Rebecca Thomas, Lana Mhaldien, Attia Hasnain, Natalia Izotova, Nina Tailor, Barry Flutter, Batoul Ahmed, Toni Braybrook, Danielle Pinner, Lindsey Williams, Ka-Yuk Ko, Anna Taylor, Adebimpe Eshilokun, Susan Staddon, Persis Amrolia, Robert Chiesa, Giovanna Lucchini, Arina Lazareva, Khushnuma Mullanfiroze, Annette Hill, Maria Finch, Rachel Mead, Lindsey Young, Christopher Abbott, Philip Ancliff, Sara Ghorashian, Sujith Samarasinghe, Anupama Rao, Jack Bartram, Vesna Pavasovic, Danny Cheng, Ayad Eddaoudi, Farzin Farzaneh, Sabine Domning, Rene Heimke, Richard Gabriel, Martin Sauer, Rita Beier, Kirste Madeleine, Cornelia Eckert, Marco Willem Schilham, Anja Magdalena Jansen-Hoogendijk, Jin Soo Kim, Daesik Kim
Journal: Science Translational Medicine (2022)

Genome editing of allogeneic T cells can provide "off-the-shelf" alternatives to autologous chimeric antigen receptor (CAR) T cell therapies. Disruption of T cell receptor α chain (TRAC) to prevent graft-versus-host disease (GVHD) and removal of CD52 (cluster of differentiation 52) for a survival advantage in the presence of alemtuzumab have previously been investigated using transcription activator-like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 editing and linked CAR expression to multiplexed DNA editing of TRAC and CD52 through incorporation of self-duplicating CRISPR guide RNA expression cassettes within the 3' long terminal repeat of a CAR19 lentiviral vector. Three cell banks of TT52CAR19 T cells were generated and cryopreserved. A phase 1, open-label, non-randomized clinical trial was conducted and treated six children with relapsed/refractory CD19-positive B cell acute lymphoblastic leukemia (B-ALL) (NCT04557436). Lymphodepletion included fludarabine, cyclophosphamide, and alemtuzumab and was followed by a single infusion of 0.8 × 10
Evolution of inflammation and immunity in a dengue virus 1 human infection model
Authors: Adam T. Waickman, Joseph Q. Lu, HengSheng Fang, Mitchell J. Waldran, Chad Gebo, Jeffrey R. Currier, Lisa Ware, Liesbeth Van Wesenbeeck, Nathalie Verpoorten, Oliver Lenz, Lotke Tambuyzer, Guillermo Herrera-Taracena, Marnix Van Loock, Timothy P. Endy, Stephen J. Thomas
Journal: Science Translational Medicine (2022)

Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics and subtropics. More than 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and more than 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. We observed a robust DENV-specific immunoglobulin A (IgA) antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV virion-specific humoral immunity. RNA sequencing analysis revealed discrete and temporally restricted gene modules that correlated with acute viremia and the induction of adaptive immunity. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.
A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus
Authors: Haoyang Li, Tierra Buck, Michelle Zandonatti, Jieyun Yin, Alex Moon-Walker, Jingru Fang, Anatoliy Koval, Megan L. Heinrich, Megan M. Rowland, Ruben Diaz Avalos, Sharon L. Schendel, Diptiben Parekh, Dawid Zyla, Adrian Enriquez, Stephanie Harkins, Brian Sullivan, Victoria Smith, Onyeka Chukwudozie, Reika Watanabe, James E. Robinson, Robert F. Garry, Luis M. Branco, Kathryn M. Hastie, Erica Ollmann Saphire
Journal: Science Translational Medicine (2022)

Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.
Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats
Authors: Tobias Kroon, Therese Hagstedt, Ida Alexandersson, Annett Ferm, Marie Petersson, Stefanie Maurer, Bader Zarrouki, Kristina Wallenius, Nicholas D. Oakes, Jeremie Boucher
Journal: Science Translational Medicine (2022)

Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.
Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis
Authors: Jayanth Kumar Narayana, Stefano Aliberti, Micheál Mac Aogáin, Tavleen Kaur Jaggi, Nur A’tikah Binte Mohamed Ali, Fransiskus Xaverius Ivan, Hong Sheng Cheng, Yun Sheng Yip, Marcus Ivan Gerard Vos, Zun Siong Low, Jeannie Xue Ting Lee, Francesco Amati, Andrea Gramegna, Sunny H. Wong, Joseph J. Y. Sung, Nguan Soon Tan, Krasimira Tsaneva-Atanasova, Francesco Blasi, Sanjay H. Chotirmall
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Emerging data support the existence of a microbial "gut-lung" axis that remains unexplored in bronchiectasis. Methods: Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of n = 57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S Internal Transcribed Spacer) sequencing (total, 228 microbiomes). Shotgun metagenomics was performed in a subset (n = 15; 30 microbiomes). Data from gut and lung compartments were integrated by weighted similarity network fusion, clustered, and subjected to co-occurrence analysis to evaluate gut-lung networks. Murine experiments were undertaken to validate specific Pseudomonas-driven gut-lung interactions. Results: Microbial communities in stable bronchiectasis demonstrate a significant gut-lung interaction. Multibiome integration followed by unsupervised clustering reveals two patient clusters, differing by gut-lung interactions and with contrasting clinical phenotypes. A high gut-lung interaction cluster, characterized by lung Pseudomonas, gut Bacteroides, and gut Saccharomyces, is associated with increased exacerbations and greater radiological and overall bronchiectasis severity, whereas the low gut-lung interaction cluster demonstrates an overrepresentation of lung commensals, including Prevotella, Fusobacterium, and Porphyromonas with gut Candida. The lung Pseudomonas-gut Bacteroides relationship, observed in the high gut-lung interaction bronchiectasis cluster, was validated in a murine model of lung Pseudomonas aeruginosa infection. This interaction was abrogated after antibiotic (imipenem) pretreatment in mice confirming the relevance and therapeutic potential of targeting the gut microbiome to influence the gut-lung axis. Metagenomics in a subset of individuals with bronchiectasis corroborated our findings from targeted analyses. Conclusions: A dysregulated gut-lung axis, driven by lung Pseudomonas, associates with poorer clinical outcomes in bronchiectasis.
Therapeutic gene editing of T cells to correct CTLA-4 insufficiency
Authors: Thomas Andrew Fox, Benjamin Christopher Houghton, Lina Petersone, Erin Waters, Natalie Mona Edner, Alex McKenna, Olivier Preham, Claudia Hinze, Cayman Williams, Adriana Silva de Albuquerque, Alan Kennedy, Anne Maria Pesenacker, Pietro Genovese, Lucy Sarah Kate Walker, Siobhan Oisin Burns, David Michael Sansom, Claire Booth, Emma Catherine Morris
Journal: Science Translational Medicine (2022)

Heterozygous mutations in CTLA-4 result in an inborn error of immunity with an autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic hematopoietic stem cell transplantation. Here, we designed a homology-directed repair (HDR) gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4 + T cells, and functional studies demonstrated CD80 and CD86 transendocytosis. Gene editing of T cells isolated from three patients with CTLA-4 insufficiency also restored CTLA-4 protein expression and rescued transendocytosis of CD80 and CD86 in vitro. Last, gene-corrected T cells from CTLA-4 −/− mice engrafted and prevented lymphoproliferation in an in vivo murine model of CTLA-4 insufficiency. These results demonstrate the feasibility of a therapeutic approach using T cell gene therapy for CTLA-4 insufficiency.
Examining Stripes on a Herd of Zebras: Impact of Genomic Matching for Ultrarare Sarcomas in Phase 1 Clinical Trials (SAMBA 102)
Authors: Justin T. Moyers, Roberto Carmagnani Pestana, Jason Roszik, David S. Hong, Aung Naing, Siqing Fu, Sarina Piha-Paul, Timothy A. Yap, Daniel Karp, Jordi Rodon, Andy Livingston, Maria Alejandra Zarzour, Vinod Ravi, Shreyaskumar Patel, Robert S. Benjamin, Joseph Ludwig, Cynthia Herzog, Ravin Ratan, Neeta Somaiah, Anthony Conley, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Recently, the Connective Tissue Oncology Society published consensus guidelines for recognizing ultrarare sarcomas (URS), defined as sarcomas with an incidence ≤1 per 1,000,000. We assessed the outcomes of 56 patients with soft tissue, and 21 with bone sarcomas, enrolled in Phase 1 trials. Experimental Design: In this Sarcoma-Matched Biomarker Analysis (SAMBA-102 study), we reviewed records from patients on Phase 1 trials at the University of Texas MD Anderson Cancer Center between January 2013 and June 2021. Results: Among 587 sarcomas, 106 (18.1%) were classified as URS. Fifty (47%) were male, and the median age was 44.3 years (range, 19–82). The most common subtypes were alveolar soft part sarcoma (ASPS), chordoma, dedifferentiated chondrosarcoma, and sclerosing epithelioid fibrosarcoma. Compared with common sarcomas, median OS was similar 16.1 months [95% confidence interval (CI), 13.6–17.5] versus 16.1 (95% CI, 8.2–24.0) in URS (P = 0.359). Objective response to treatment was higher in URS 13.2% (n = 14/106) compared with common sarcomas 6.9% (n = 33/481; P = 0.029). Median OS for those treated on matched trials was 27.3 months (95% CI, 1.9–52.7) compared with 13.4 months (95% CI, 6.3–20.6) for those not treated on matched trials (P = 0.291). Eight of 33 (24%) molecularly matched treatments resulted in an objective response, whereas 6 of 73 unmatched treatments (8.2%) resulted in an objective response (P = 0.024). Clinical benefit rate was 36.4% (12/33) in matched trials versus 26.0% (19/73) in unmatched trials (P = 0.279). Conclusions: The results demonstrate the benefit of genomic selection in Phase 1 trials to help identify molecular subsets likely to benefit from targeted therapy.
TssI2-TsiI2 of <i>Vibrio fluvialis</i> VflT6SS2 delivers pesticin domain-containing periplasmic toxin and cognate immunity that modulates bacterial competitiveness
Authors: Yuanming Huang, Yu Han, Zhenpeng Li, Xiaorui Li, Zhe Li, Ping Liu, Xiaoshu Liu, Qian Cheng, Fenxia Fan, Biao Kan, Weili Liang
Journal: Gut Microbes (2022)

Vibrio fluvialis is a halophilic Gram-negative bacterium regarded as an emerging unusual enteric pathogen of increasing public health concern. Our previous work has identified two type VI secretion systems (T6SSs) in V. fluvialis, VflT6SS1, and VflT6SS2, and the latter is functional in mediating interbacterial competitiveness. However, its antibacterial effectors remain to be clarified. In this work, we focused on a new potential effector/immunity pair TssI2/TsiI2. Bioinformatics analysis revealed that the C-terminal domain of TssI2 belongs to a widespread family of pesticin, and its antibacterial toxicity and corresponding protection by TsiI2 were proved via bacterial killing assays, and their action sites were localized to the periplasm of bacterial cells. The interaction of TssI2 and TsiI2 was demonstrated by the bacterial adenylate cyclase two-hybrid, protein pull-down and isothermal titration calorimetry assays. Site-directed mutagenesis demonstrated that, in addition to Glu-844, Thr-863, and Asp-869, which correspond to three reported residues in pesticin of Yersinia pestis, additional residues including Phe-837, Gly-845, Tyr-851, Gly-867, Gln-963, Trp-975, and Arg-1000 were also proved to be crucial to the bactericidal activity of TssI2. Muramidase/lysozyme-related peptidoglycan (PG) hydrolase activities of TssI2 and its variants were validated with permeabilized Escherichia coli cells and purified PG substrate. Based on sequence homologies at C-terminals in various V. fluvialis isolates, TssI2 was subdivided into five clusters (12–22% identity among them), and the antibacterial activities of representative effectors from other four Clusters were also confirmed through periplasmic over-expression in E. coli host. Two selected cognate immunities were proved to confer protection against the toxicities of their effectors. Additionally, TsiI2, which belongs to Cluster I, exhibited cross-protection to effector from Cluster V. Together, current findings expand our knowledge of the diversity and consistency of evolved VgrG effectors in V. fluvialis and on how VflT6SS2 mediates a competitive advantage to gain a better survival.